Neuropharmacology of Parkinson's

Question 1

Dopamine is the main neurotransmitter involved in Parkinson’s, where in the brain does it take effect?

Answer 1

Brain stem - Vomiting Centres
Basal Ganglia - Initiating/Controlling Movement
Limbic System & Frontal Cortex - Reward Centres

Question 2

How does Parkinson’s happen again?

Answer 2

Loss of dopaminergic nigrostriatal fibres in the substantia nigra. Causing a dopamine deficiency in the basal ganglia.

Question 3

How/where is dopamine synthesised?

Answer 3

Dopamine is synthesised in both the brain and periphery but only its precursors can cross the BBB.

Tyrosine -> DOPA -> Dopamine

Question 4

If Dopamine itself can’t cross the BBB how do we deliver it as a drug?

Answer 4

We give DOPA as a precursor.
We have to block the AAAD enzyme in the liver to prevent the DOPA being converted to dopamine before it reaches the Brain

Question 5

Explain the variety of dopamine receptors?

Answer 5

D1-D5 receptors (All metabotropic i.e. G-protein coupled)

Different receptors appear in different parts of the brain

Question 6

What drug categories are there for Parkinson’s?

Answer 6

Dopamine Precursors
Dopamine Agonists
Dopamine breakdown Inhibitors (used to extend half life of levodopa)

Question 7

What enzymes are targeted by Dopamine breakdown Inhibitors?

Answer 7

MAO-B

COMT

Question 8

What is used as a dopamine precursor?

Answer 8

Levodopa

Question 9

What does it mean to say Levodopa has a “half Life”?

Answer 9

It becomes progressively less effective over time as dopaminergic neurons are lost and the brain can no longer convert it to dopamine

Question 10

How do we extend levodopa’s half life?

Answer 10

With Dopamine breakdown Inhibitors acting on MAO-B and COMT

Question 11

List some dopamine breakdown inhibitors?

Answer 11

MAO-B inhibitors:
Selegiline, Rasagiline & Safinamide

COMT inhibitors:
Entacapone & Tolcapone

Question 12

We also use enzyme inhibitors to reduce Levodopa consumption in the periphery, how and why?

Answer 12

Carbidopa & Benserazide are AAAD inhibitors preventing conversion of Levodopa -> Dopamine in the periphery.

This allows more oral levodopa to reach the brain and reduces PNS side effects

Question 13

List some dopamine agonists?

Answer 13

Ergots - Stimulate fibrosis and very dirty so no longer in use
Non-ergots - Not as effective as Levodopa
Apomorphine - Heavily stimulates brainstem dopamine receptors making it a powerful emetic

Question 14

What are the benefits of dopaminergic drugs?

Answer 14

Improves motor features of parkinson’s:

• Bradykinesia
• Rigidity
• Tremor

But doesnt improve things like cognition, balance or dysarthia

Question 15

What are the side effects of dopaminergic drugs?

Answer 15

Brainstem - N/V

Limbic system/frontal lobe - Psychosis and impulsive/abnormal behaviours

Question 16

Given the side effects of dopaminergic drugs, what could dopamine antagonists be used for?

Answer 16

N&V

Long-term psychosis treatment

Question 17

What is the obvious side effect of Dopamine antagonists?

Answer 17

Parkinson’s Syndrome, hence they really shouldnt be used in people with parkinsons in the first place

Question 18

Domperidone is a notable dopamine antagonist, what is it used for?

Answer 18

As an anti-emetic because it doesnt cross the BBB, but the vomiting centre in the medulla is actually outside it.

This means domperidone won’t treat psychosis but will be anti-emetic without worsening parkinson’s.

Hence its used in conjunction with apomorphine to prevent the emetic effect of the dopamine agonist